Tumor necrosis factor-alpha (TNF-alpha, also known as cachectin) is a mammalian protein capable of inducing a variety of effects on numerous cell types. TNF-alpha was initially characterized by its ability to cause lysis of tumor cells, and is produced by activated cells such as mononuclear phagocytes, T-cells, B-cells, mast cells and NK cells. Because the deleterious effects which can result from an over-production or an unregulated production of TNF are extremely serious, considerable efforts have been made to control or regulate the serum levels of TNF.
The numerous biological effects of TNF-alpha and the closely related cytokine TNF-beta (lymphotoxin), are mediated by two transmembrane receptors, both of which have been cloned. The 55 receptor, also termed TNF-R55, TNF-RI, or TNFRbeta, is a 55 kd glycoprotein which has been shown to transduce signals resulting in cytotoxic, anti-viral, and proliferative activities of TNF-alpha.
The p75 receptor, also termed TNF-R75, TNF-RII, or TNFRalpha, is a 75 kd glycoprotein that has also been shown to transduce cytotoxic and proliferative signals as well as signals resulting in the secretion of GM-CSF. The extracellular domains of the two receptors are 28% identical in primary structure and have in common a set of four subdomains defined by numerous conserved cysteine residues. The p75 receptor differs, however, by having a region adjacent to the transmembrane domain that is rich in proline residues and contains sites of O-linked glycosylation. The cytoplasmic domains of the two receptors share no apparent homology, which is consistent with observations that they can transduce different signals to the interior of the cell.
There are currently two drugs which have been approved for treatment of rheumatoid arthritis that act by neutralizing the activity of secreted TNF: etanercept (ENBREL), which is based on a p75:pC receptor and a humanized monoclonal antibody that neutralizes the activity of TNF, such inflixamab (REMICADE). Etanercept, or ENBREL, is an extracellular ligand binding protein of the human p75 TNF receptor (TNF-R) linked to the Fc portion of human IgG1. Infliximab, or REMICADE, is a humanized monoclonal antibody that neutralizes the activity of secreted TNF. Both ENBREL (Etanercept) and REMICADE (Infliximab) potently bind TNF and block inflammation by inhibiting the downstream effect of this cytokine. ENBREL (Etanercept) can bind to lymphotoxin alpha as well as to TNF.
Hepatitis is an inflammatory disorder which can to be caused by viral infections, including Epstein-Barr, cytomegalovirus, and hepatitis A-E viruses. Hepatitis causes acute liver inflammation in the portal and lobular region, followed by fibrosis and tumor progression.
Rheumatoid arthritis is a chronic, progressive and debilitating disease characterized by polyarticular joint inflammation and destruction, with systemic symptoms of fever and malaise and fatigue. Rheumatoid arthritis also leads to chronic synovial inflammation, with frequent progression to articular cartilage and bone destruction.
ENBREL (Etanercept) has been reported to have several side effects, which include possible exacerbation of bacterial infections, including sepsis.